Recent studies have suggested a link between insulin resistance, increased sympathetic nervous system activity and obesity hypertension. On the basis of our own preliminary data and the human and animal data available in the literature, we hypothesize that central nervous system activation of the sympathetic nervous system maybe responsible for both insulin resistance and hypertension observed in our obese dog model. We should be able to determine what portions of the sympathetic nervous system are responsible for the insulin resistance and hypertension observed in obese dogs, by placing the dogs, before and during the development of obesity, on three different sympathetic agents (clonidine that works centrally, prazosin a peripheral alpha-receptor blocker and atenolol a beta receptor blocker). Insulin mediated glucose uptake is determined both by insulin's ability to stimulate glucose extraction at the level of tissues/cells and by the rate of glucose and insulin's delivery (blood flow). Therefore, the relative contributions of tissue and blood flow actions of insulin will determine the overall rate of glucose uptake (i.e., degree of insulin resistance). In the current proposal we will determine if the insulin resistance associated with obesity in the dog is due to an impairment in insulin's action to increase blood flow and/or to an impairment of insulin to stimulate glucose extraction at the tissue level. We plan to accomplish this specific aim by evaluating the effect of three different insulin infusion levels (euglycemic clamps) to alter regional (leg and cardiac muscular) blood flow (measured by Doppler flow probes) and tissue extraction (arteriovenous difference in glucose). We will also be able to determine how each of the sympathetic agents affects insulin's ability to alter blood flow and the tissue extraction of glucose. Finally we will determine if obesity produces insulin resistance in both skeletal and cardiac muscles. We believe that the results of these experiments will help us to understand why obesity is an important risk factor for the development of both diabetes and cardiovascular disease.